Core B: Computational Systems Pharmacology Project Summary The Computational Systems Pharmacology Core (Core B) will provide computational biology and quantitative systems pharmacology (QSP) support to Projects 1-3. The Core will contribute to the research goals of the P01 in three major ways: identification of targets (proteins, pathways or networks) implicated in ATZ accumulation (Specific Aim 1); quantitative modeling and analysis of the cellular networks identified to be associated with ATZ elimination, and systematic interrogation of these networks to generate plausible hypotheses for (poly)pharmacological strategies (Specific Aim 2); and refinement of drug candidates discovered in the first term (e.g. glibenclamide and its analog G2, cyclodextrin family members, and selected agonists of mucolipins) and identification of new testable candidates (both repurposable drugs and new compounds) to assist in the design and development of mechanism-based ATD therapeutics (Specific Aim 3). In line with the progress and contributions made in the first term, the Core will analyze high-throughput/content (RNAi, EMS chemical mutagenesis, and small-molecule library screening) data collected by Project 2 and gene expression profile data of ATZ-expressing iPS cells (Project 3). Quantitative model construction and analyses will support Project 1 team to assess (i) the cell signaling and regulation mechanisms that predominantly determine the cell fate in response to the proteotoxic effect of ATZ accumulation, with focus on autophagic, proteostasis and calcium signaling pathways; (ii) the pathophysiological effects of sequence variants detected in cohort exome sequencing studies (in coordination with Project 3); (iii) optimal modifications of drug candidates to increase their potency, and particular combination therapies (e.g. prochlorperazine and amlodipine) that may act synergistically. The Core will use a broad range of machine learning algorithms, and bioinformatics, cheminformatics, QSP and molecular modeling methods, tools and software developed by the Core members as well as relevant databases and software publicly available.